FK506 is a potent immunosuppressant used to prevent rejection of transplanted organs in humans. Non-immunosuppressant analogs of FK506 have been shown to promote regeneration of damaged nerves, raising the possibility for their use in the treatment of a variety of neurodegenerative disorders. However, the bioavailability of FK506 varies considerably between individuals due to variable metabolism by cytochrome P450 enzymes. The long term goal of this project is to produce analogs of FK506 that are non-immunosuppressant, are fully active in stimulating nerve regeneration, and are more resistant to Cy P450 degradation. We will engineer the biosynthetic genes for FK520 (related to FK506) in a FK520-producing Streptomyces strain, so that it produces the analogs; a technology that is well established at Kosan Biosciences. These analogs would be very difficult to obtain by other means. The analogs will be produced and compared to the parent FK520 molecule for susceptibility to P450 degradation and for toss of immunosuppressive activity in vitro. Nerve regeneration studies will be included in an anticipated phase II application. The proposed analogs would be novel and have the potential for neurotrophic activity that could improve the quality of life for a growing sector of the population suffering from neurodegenerative disorders. PROPOSED COMMERCIAL APPLICATION: Neurodegenerative diseases such as Alzheimer's, ALS and Parkinson's, have no known cure. CNS injuries such as spinal cord trauma and stroke are irreversible. These conditions have devastating effects on the individuals involved, and have a considerable impact on the US economy. As the baby boomer generation ages, the demand for treatments will increase. The current lack of any efficacious pharmaceutical treatments for the restoration of nerve activity means that any therapeutic drug developed will have considerable commercial impact. Market analysis estimates the potential opportunity in today's US market to be 2.2 billion.